“Obsessive-compulsive spectrum disorders” is an overarching category of disorders that includes a variety of compulsive, impulsive, and pervasive developmental disorders. These disorders share features with obsessive-compulsive disorder, including symptoms such as repetitive thoughts and behaviors. Obsessive-compulsive disorder (OCD) is one disorder that may be included within this category. Other disorders that are included within this category are listed herein, and include somatoform disorders, eating disorders, impulse control disorders, movement disorders including Tourette's syndrome and Sydenham's chorea, and pervasive developmental disorders, including autism, Asperger's syndrome and Pervasive Developmental Disorder not otherwise specified (PDD-NOS).
Obsessive-compulsive disorder (OCD) is now recognized as a common disorder that has a life-time prevalence in the United States ranging from 1.9% to 3.3% (Shapira et al., Depression and Anxiety 6; 170-173 (1997).) There are a number of well-recognized diagnostic criteria for OCD (Diagnostic and Statistical Manual of Mental Disorders, fourth edition; DSM-IV). Such criteria include obsessions or compulsions, which the individual has, at some point during the course of the disorder recognized, that the obsessions or compulsions are excessive or unreasonable; the obsessions or compulsions caused marked stress, are time-consuming or significantly interfere with the person's normal routine, occupational/academic functioning, or usual social activities or relationships; if another axis I disorder is present, the content of the obsessions or compulsions is not restricted to it; and the disturbance is not due to the direct physiologic effects of a substance or a general medical condition.
According to the DSM-IV, indicia of obsessions include the person having recurrent and/or persistent thoughts, impulses or images that are experienced at some time during the disturbance as intrusive and inappropriate and as causing marked anxiety or distress. Typically, the thoughts, impulses or images are not simply excessive worries about real-life problems. Third, the person attempts to ignore or suppress such thoughts, impulses or images or to neutralize them through some other thought or action. Fourth, the person recognizes that the obsessional thoughts, impulses, or images are products of his or her own mind and are not imposed from without.
The DSM-IV also sets forth diagnostic criteria as indicia of compulsion. In compulsive disorders, the person has repetitive behaviors or mental acts that the person feels driven to perform in response to an obsession or according to rules that must be applied rigidly. Repetitive behaviors include hand washing, ordering and checking, while mental acts include praying, counting and repeating words silently. Second, the behaviors or mental acts are aimed at preventing some dreaded event or situation; however, these behaviors or mental acts either are not connected in a realistic way to what they are designed to neutralize or prevent, or are clearly excessive.
Individuals who meet the DSM-IV criteria for OCD can be scored using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Y-BOCS scores range from 0 to 40. Generally, 0 to 7 is considered a subclinical syndrome, 8-15 is considered mild, 16-23 is considered moderate, 24-31 is considered severe, and 32-40 is considered extremely severe. This scale is further discussed in e.g., U.S. Pat. No. 6,387,956 (incorporated herein by reference in its entirety). Other U.S. patents that generally provide discussion of methods of evaluating and treating OC disorders include e.g., U.S. Pat. No. 6,420,351; U.S. Pat. No. 6,410,527; U.S. Pat. No. 6,632,429; U.S. Pat. No. 6,716,416; U.S. Pat. No. 6,667,297; and U.S. Pat. No. 6,512,010. Each of these patents is incorporated herein by reference in its entirety.
A wide range of psychiatric and neuropsychiatric disorders appear to be related to OCD and form a family of related disorders referred to as obsessive-compulsive (OC) spectrum disorders. OC spectrum disorders include somatoform disorders, eating disorders, impulse control disorders (ICDs), paraphilia and nonparaphilic sexual addictions, Sydeham's chorea, torticollis, autism, and movement disorders, including Tourette's syndrome.
Somatoform disorders include body dysmorphic disorder (BDD) and hyperchondriasis. Body dysmorphic disorder (BDD) is a preoccupation with an imagined slight defect in appearance that causes significant distress or impairment in functioning. Individuals suffering from BDD have preoccupations similar to OCD obsessions in that they have repetitive intrusive thoughts, often perform time-consuming, repetitive and sometimes ritualistic behaviors. Hypochondriasis is a preoccupation with the fear of having, or the idea that one has, a serious disease based on the person's misinterpretation of bodily signs or symptoms. Hypochondriacal preoccupations resemble OCD obsessions in that they are often experienced as intrusive and persistent, and the individuals often display repetitive checking behaviors.
Eating disorders include anorexia nervosa, bulimia nervosa and binge eating disorder (BED). The DSM-IV defines anorexia nervosa as a refusal to maintain a minimally normal body weight; intensive fear of gaining weight or becoming fat even though underweight; significant disturbance in perception of body shape or size; and, in females, amenorrhea. The DSM-IV defines bulimia nervosa as recurrent episodes of binge eating followed by inappropriate compensatory behaviors designed to prevent a weight gain. BED is characterized by recurrent episodes of binge eating in the absence of regular use of inappropriate compensatory behaviors. There is some overlap among anorexia nervosa, bulimia nervosa, and BED. However, all three disorders are characterized by a core preoccupation with food and body weight. Individuals suffering from eating disorders often perform specific rituals, and have an abnormal preoccupation with food and weight.
The DSM-IV defines an impulse control disorder (ICD) as the failure to resist the impulse, drive or temptation to perform some act that is harmful. ICDs include intermitted explosive disorder (IED), compulsive buying or shopping, repetitive self-mutilation (RSM), onychophagia, psychogenic excoriation, kleptomania, pathological gambling, and trichotillomania. Most individuals suffering from ICDs experience increasing sense of tension or arousal before committing the act, followed by pleasure, gratification or relief at the time of committing the act. Individuals suffering from ICD often experience impulses which are intrusive, persistent and associated with anxiety or tension. Individuals suffering from paraphilias and nonparaphilic sexual addictions (NPSAs) experience similar increasing senses of tension or arousal before committing the act, followed by pleasure, gratification or relief at the time of committing the act.
Tourette's syndrome is a chronic neuropsychiatric disorder characterized by motor tics and one or more vocal tics beginning before the age of 18 years. The DSM-IV defines a tic as a sudden, rapid, recurrent, non-rhythmic, stereotyped motor movement or vocalization. Tourette's syndrome patients may be able to suppress tics for varying lengths of time, but eventually experience them as irresistible and perform them. Tourette's patients exhibit obsessions resembling OCD obsessions, for example, they often feel the need to perform tics until they are felt to be “just right.”
Autism is characterized by difficulties with social interaction, speech and communication, and by a compulsive core. Autistic individuals often display compulsive, repetitive behaviors. First described by Kanner in 1943, autism affects social and communicative abilities and is also characterized by compulsive/repetitive behaviors such as stereotypic complex hand and body movements, craving for sameness, and narrow repetitive interests (American Psychiatric Press, 1994 DSM-IV). In addition, there is high comorbidity with inattention-hyperactivity, impulsivity and aggression, self injury, mood instability, mental retardation and epilepsy, making care for these individuals an even greater challenge for families and institutional settings.
Autism belongs to a group of pervasive developmental disorders (PDD) as characterized by both DSM IV and World Health Organization: International Classification of Diseases, Tenth revision (ICD-10)). In addition to autism, PDDs include Asperger's, ADD, and ADHD. PDDs are typically characterized by multiple distortions in the development of basic psychological functions that are involved in the development of social skills and language, such as attention, perception reality testing and motor movement. In addition, many children diagnosed with Autism, for example, suffer from primary diffuse gastrointestinal problems such as protracted diarrhea and constipation. Although PDDs are currently of unknown etiology, many conventional methods, such as dietary alteration, behavioral modification, and medication, have been utilized for treating individuals suffering from PDD related disorders. Unfortunately, PDD related disorders have no known treatment beyond that which is symptomatic, and these conventional methods have proven unsuccessful in allowing such children and adults to become symptom- or disorder-free.
A child which displays signs of developmentally inappropriate inattention, impulsivity and hyperactivity is typically diagnosed as having ADD and/or ADHD. With these disorders, there can be marked disturbances of organization, distractibility, impulsivity, restlessness, and other disturbances of language and/or social behavior. A combination of psychiatric care and medicine is typically used for treating children with ADD and ADHD.
Behavior modification therapy is often efficacious in treating obsessive-compulsive spectrum disorders, including OCD. However, behavior modification therapy generally requires prolonged periods of treatment. Also, an individual may not respond favorably to behavior modification therapy unless the severe OC spectrum disorder symptoms are first controlled or decreased. Thus, it is often desirable to supplement the initial stages of behavior modification with drug therapy. Preferably, the drug therapy will be one that has a short onset of action, preferably less than two weeks.
Some OC spectrum disorders, such as bulimia nervosa, have been shown to respond to monoamine oxidize inhibitors (MAOIs). Unfortunately, people who use MAOIs are forced to adhere to numerous dietary restrictions and observe special precautions to avoid drug interactions.
OCD has been treated with serotonin reuptake inhibitors (SRIs) such as clomipramine, fluoxetine, fluvoxamine, sertraline and paroxetine. There is also evidence to suggest that Tourette's syndrome, hypochondriasis, anorexia nervosa, and ICDs such as intermitted explosive disorder (IED), kleptomania, pathological gambling, trichotillomania, compulsive shopping, onychophagia and psychogenic excoriation may respond to SRIs. (Goldsmith et al., Conceptual Foundations of Obsessive-Compulsive Spectrum Disorder, in Obsessive-Compulsive Disorder, Richard P. Swinson et al. Editors, The Guilford Press. pages 397-425 (1998).) SRIs have also been used to treat compulsive symptoms in autism. (Hollander, J. Clim. Psychiatry, 58(12): 3-6 (1997).)
Unfortunately, some individuals are refractory to serotonin reuptake inhibitors. Approximately 30 to 50% of individuals do not respond at all to serotonin reuptake inhibitors, while many who do respond do so only partially. Further, serotonin reuptake inhibitors have a slow onset of action and often require eight to ten weeks of treatment to achieve a significant reduction in symptoms. Also, individuals suffering from movement disorders, such as Tourette's syndrome, often desire a drug that can be taken pro re nata (on an as-needed basis).
It was recently discovered that the administration of secretin, a gastrointestinal peptide hormone, to children diagnosed with Autism resulted in ameliorating the symptoms associated with Autism. This finding was published in the article by Horvath et al., entitled Improved Social and Language Skills After Secretin Administration In Patients with Autistic Spectrum Disorders, Journal of the Association for Academic Minority Physician Vol. 9 No. 1, pp. 9-15, January, 1998. The secretin administration, as described in Horvath, was performed as a diagnostic procedure, i.e., to stimulate pancreaticaobiliary secretion during an upper gastrointestinal endoscopy, rather than as a therapeutic procedure. Although the specific mechanism by which the secretin improved the autistic-related symptoms was not specifically identified, Horvath postulated that secretin may have had a direct or indirect effect on the central nervous system. What is important, however, is that this was the first time that gastrointestinal problems of autistic children were linked to a possible etiology in Autism.
Memantine has recently been approved by FDA for the treatment of memory loss in Alzheimer's disease, a neurodegenerative disorder of the nervous system. This approval was based on three randomized placebo-controlled trials that showed significant improvements in cognitive, functional and global endpoints in this population (Tariot et al., JAMA. 2004; 291:317-24, Reisberg et al, N Engl J Med., April 3; 348(14): 1333-41 (2003), Winblad et al., Int J Geriatr Psychiatry, 14(2): 135-46 (1999)). Similar results were seen in two trials in vascular dementia (Wilcock et al., Int Clin Psychopharmacol., 17(6): 297-305(2002), Orgogozo et al., Stroke, 33:1834-9 (2002)). Memantine has been used in Germany for a variety of neurological syndromes and cognitive deficits since 1982 with good tolerability. In animal models, memantine has been shown to prolong the duration of long term potentiation in vivo and to improve learning and memory. (Zajaczkowski et al., Eur J Pharmacol., 296(3): 239-46 (1996)). Neuroprotection has been demonstrated in animals (Danysz et al., Amino Acids., 19(1): 167-72 (2000)) but the clinical data is still pending.
Autism, unlike Alzheimer's disease, is a neurodevelopmental disorder rather than neurodegenerative disease.
There are currently no drugs approved for the treatment of autism and other PDDs. Serotonin reuptake inhibitors have been shown to have some effect on repetitive behaviors. Atypical antipsychotics seem to be effective in the treatment of aggression. Antiepileptic medications may be useful for aggression, especially in children with epileptiform abnormalities. Amantadine, a weak inhibitor of the NMDA glutamate receptor, has been tested in autism. The study showed some improvement in irritability and hyperactivity; however, amantadine has a very weak affinity for this receptor and therefore very high doses would be required to get an adequate effect. Memantine is a newly approved medication for the treatment of cognitive decline in Alzheimer's disease. It has moderate affinity for the NMDA receptor and has properties such as rapid blocking/unblocking abilities that render it very well tolerated.
Thus while numerous degenerative disorders may be treated with a variety of therapies, numerous developmental disorders, for example autism, remain untreatable with modern medicines.